Cerebellar cognitive affective syndrome with long-term features of autism spectrum disorder: evidence in a 9-year-old girl after vermian medulloblastoma surgery.

The time course of socio-communicative disturbances in children after posterior fossa tumor resection is variable in clinical reports, and its assessment may help to understand the role of the cerebellum in the pathogenesis of socio-communicative disorders and improve rehabilitation plans. We report the 3-year cognitive-behavioral follow-up of a female patient (LZ) who underwent surgical ablation of the vermis due to medulloblastoma at age 9. LZ developed a severe post-operative Cerebellar Cognitive Affective Syndrome (CCAS) with cognitive-executive dysfunctions and behavioral alterations resembling an Autism Spectrum Disorder (ASD)-like syndrome. The lack of empathy and reduced ability to recognize others' intentions and mental states persisted at follow-up evaluations, as did language alterations. The present case report evidenced that lesions affecting cerebellar and vermal lobules may cause severe CCAS and impairment of social skills overlapping with that observed in ASD. This case is significant in its clinical features, revealing long-term social impairment, while the cognitive, linguistic, and executive functioning improved over time. Prospective case studies should plan the evaluation of symptoms of ASD within the clinical longitudinal assessment.

Post Surgical Management of WHO Grade II Meningiomas: Our Experience, the Role of Gamma Knife and a Literature Review.

Purpose: Grade II meningiomas are rarer than Grade I, and when operated on, bear a higher risk of local recurrence, with a 5-year progression free survival (PFS) ranging from 59 to 90%. Radiotherapy (RT) or radiosurgery, such as Gamma Knife radiosurgery (GKRS) can reduce the risk of relapse in patients with residual disease, even if their role, particularly after gross total resection (GTR), is still under debate. Main goal of this study was to compare the outcomes of different post-surgical management of grade II meningiomas, grouped by degree of surgical removal (Simpson Grade); next in order we wanted to define the role of GKRS for the treatment of residual disease or relapse. Methods: from November 2016 to November 2020 all patients harboring grade II meningiomas, were divided into three groups, based on post-surgical management: (1) wait and see, (2) conventional adjuvant radiotherapy and (3) stereotactic GKRS radiosurgery. Relapse rate and PFS were registered at the time of last follow up and results were classified as stable, recurrence next to or distant from the surgical cavity. In the second part of the study we collected data of all patients who underwent GKRS in our Centers from November 2017 to November 2020. Results: A total of 37 patients were recruited, including seven patients with multiple meningiomas. Out of 47 meningiomas, 33 (70.2%) were followed with a wait and see strategy, six (12.7%) were treated with adjuvant radiotherapy, and 8 patients (17.0%) with adjuvant GKRS. Follow up data were available for 43 (91.4%) meningiomas. Within the wait and see group, recurrence rates differed based on Simpson grades, lower recurrence rates being observed in three Simpson I cases (30%) compared to twelve relapses (60%) in patients with Simpson grade II/III. Finally, out of the 24 meningiomas undergoing GKRS (8 residual and 16 recurrence), 21 remained stable at follow up. Conclusions: Gross total resection (GTR) Simpson II and III have a significantly worse outcome as compared to Simpson I. The absence of adjuvant treatment leads to significant worsening of the disease progression curve. Adjuvant radiotherapy, especially GKRS, provides good local control of the disease and should be considered as an adjuvant treatment in all cases where Simpson I resection is not possible.

Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome.

The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887&897.

Long-term outcome of moderate hypofractionated stereotactic radiotherapy for meningiomas.

PURPOSE: The aim of this work was to evaluate long-term results of moderate hypofractionated stereotactic radiotherapy (hFSRT) for intracranial meningiomas. PATIENTS AND METHODS: In all, 77 consecutive patients with 80 lesions were included. Median age was 65 years (range 23-82 years), male/female ratio was 21/56, and the median Karnofsky performance status was 90 (range 60-100). In 31 lesions (39 %), diagnosis was based upon clinical and radiological data; 37 lesions were histologically proven as World Health Organization (WHO) grade I and 12 grade II meningiomas. Median treatment volume was 23 cc. Prescribed doses were 45 Gy in 15 fractions of 3 Gy (15 × 3 Gy) or 42 Gy in 14 fractions of 3 Gy (14 × 3 Gy). RESULTS: After a median follow-up of 56 months, 49 (61 %) lesions received 14 × 3 Gy and 31 (39 %) 15 × 3 Gy. Local control (LC) rate remained unchanged at 84 % at 5 and 10 years. Overall survival and disease-specific survival (DSS) were 76 and 93 % at 5 years, 72 and 89 % at 10 years, respectively. With univariate analysis, previous surgery and WHO grade II tumor were negative prognostic factors for LC and DSS. With multivariate analysis only tumor grade was an independent prognostic factor for LC. No clinically significant acute and/or late toxicities were observed. CONCLUSION: Moderate hFSRT was effective and safe with an excellent tolerance profile. It can be an alternative treatment option for patients with recurrent or inoperable large meningiomas. The low number of fractions administered with hFSRT led to reduce treatment-related discomfort for patients. Grade II tumor and previous surgery were negative prognosis factors.

Human neural stem cell transplantation in ALS: initial results from a phase I trial.

BACKGROUND: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. METHODS: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. RESULTS: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. CONCLUSIONS: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material. TRIAL REGISTRATION: EudraCT:2009-014484-39 .

Reirradiation of brain metastases with radiosurgery.

PURPOSE: To assess the outcome of reirradiation with stereotactic radiosurgery (SRS) of brain metastases (BM) recurring after whole brain radiotherapy (WBRT). METHODS AND MATERIALS: Between September 2001 and October 2008, 69 patients who recurred after WBRT were re-irradiated with SRS using a linear accelerator. The dose prescription was generally chosen according to maximum diameter of the tumor as suggested by Radiation Therapy Oncology Group (RTOG) 90-05 protocol. Patients were stratified by Karnofsky Performance Status (KPS), Neurologic Functional Score (NFS), RTOG Recursive Partitioning Analysis (RPA), Score Index for Radiosurgery (SIR), primary disease, dimension and number of BM, and time to first brain recurrence after WBRT. Response, survival, and toxicity were analyzed. RESULTS: At time of this retrospective analysis all patients had died. The 69 patients reirradiated with SRS had 150 metastases. Median interval between prior WBRT and SRS was 11 months and median SRS prescribed dose was 20 Gy. Response was obtained in 91% of lesions with 1-year local control rate of 74±4%. Significantly longer duration of response was associated with higher doses (≥23 Gy) and response achieved after SRS (complete and partial response better than stable disease). Cause of death was brain failure only in 36 (52%) patients. Median overall survival after reirradiation was 10 months. Variables which significantly conditioned survival were KPS and NFS. Four (6%) patients had asymptomatic radionecrosis that developed prevalently when lesion diameters were larger and cumulative doses exceeded the values recommended by RTOG 90-05 protocol. About three-fourth of the patients had a good KPS and NFS after reirradiation. CONCLUSIONS: Reirradiation of BM with SRS resulted feasible and effective. A correct patient selection and an accurate evaluation of the cumulative irradiation dose were suggested.

Treatment of recurrent glioblastoma with stereotactic radiotherapy: long-term results of a mono-institutional trial.

AIMS AND BACKGROUND: Few clinical data exist concerning normal brain tissue tolerance to re-irradiation. The present study evaluated long-term outcome of 22 recurrent glioblastoma patients re-irradiated with radiosurgery or fractionated stereotactic radiotherapy. METHODS: Twenty-two patients were treated with radiosurgery (13, 59%) or fractionated stereotactic radiotherapy (9, 41%) for 24 lesions of recurrent glioblastoma. The male/female ratio was 14:8, median age 55 years (range, 27-81), and median Karnofsky performance status 90 (range, 70-100). The majority of the cases (77%) was in recursive partitioning analysis classes III or IV Radiosurgery or fractionated stereotactic radiotherapy was chosen according to lesion size and location. RESULTS: Median time between primary radiotherapy and re-irradiation was 9 months. Median doses were 17 Gy and 30 Gy, whereas median cumulative normalized total dose was 141 Gy and 98 Gy for radiosurgery and fractionated stereotactic radiotherapy, respectively. All patients submitted to radiosurgery had a cumulative normalized total dose of more than 100 Gy, whereas only a few (44%) of fractionated stereotactic radiotherapy patients had a cumulative normalized total dose exceeding 100 Gy. Median follow-up from re-irradiation was 54 months. At the time of analysis, all patients had died. After re-irradiation, 1 (4%) lesion was in partial remission, 16 (67%) lesions were stable, and the remaining 7 (29%) were in progression. Median duration of response was 6 months, and median survival from re-irradiation 11 months. Three of 13 (23%) patients submitted to radiosurgery developed asymptomatic brain radionecrosis. The cumulative normalized total dose for the 3 patients was 122 Gy, 124 Gy, and 141 Gy, respectively. In one case, the volume of the lesion was large (14 cc), and in the other 2 the interval between the first and second cycle of radiotherapy was short (5 months). CONCLUSIONS: Re-irradiation with radiosurgery and fractionated stereotactic radiotherapy is feasible and effective in recurrent glioblastoma patients. Apart from the importance of an accurate patient selection, cumulative radiotherapy dose and a correct indication for radiosurgery or fractionated stereotactic radiotherapy must be taken into account to avoid brain toxicity.

Cognition before and after chemotherapy alone in children with chiasmatic-hypothalamic tumors.

Studies on adults with cancer, with or without CNS involvement, have shown that chemotherapy (CT) can affect cognitive functions. Two studies on children with optic pathway gliomas, involving the hypothalamus in some cases, and treated with CT according to various protocols reported the children maintaining a good IQ (no other cognitive abilities were tested). Among 18 children with chiasmatic-hypothalamic tumors (CHT) given front-line CT treatment at our institute using the same protocol (cisplatin and etoposide), we screened eight children for cognitive sequelae, correlating their test performance with several clinical variables (age at diagnosis and at time of treatment, time elapsing since treatment, and tumor volume reduction). The neuropsychological evaluation involved measuring IQ in all eight children and cognitive flexibility in three before CT (T1), then testing IQ, attention, memory and executive functions after CT (T2). The group as a whole showed no signs of any decline in IQ from T1 to T2, except for some WISC items, but IQ deteriorated severely in three patients with NF1 (only suspected in one case). At T2, the whole sample performed within normal range, except for two children showing a significantly worse result in two specific tests. The parents of the other 10 children, reported no substantial changes in their children's behavior and intellectual vivacity in a semistructured telephone interview conducted in cooperation with the children's teachers. CT alone as front-line treatment for CHT does not appear to have a negative effect on IQ and numerous neuropsychological tests. Some skills were more affected than others in our sample (albeit with a very low statistical significance of the impairment), and some patients seemed to be more vulnerable than others after CT. The multifactorial origin of such cognitive impairments is discussed. This type of study needs to be repeated in larger, but nonetheless carefully selected groups of patients.